The goal of this Program Project is to prevent disease in the elderly upon reactivation of varicella zoster virus (VZV), the most common virological cause of disease associated with aging. By 2050, >83 million Americans will be over 65 years old with 95% harboring latent VZV. As the immune system ages, VZV will reactivate in >50% to produce zoster (shingles) complicated by postherpetic neuralgia, as well as serious multisystem disorders with or without rash including dementia, stroke, giant cell arteritis, vision loss, burning mouth syndrome, myocardial infarction, and bowel and bladder dysfunction. While zoster vaccine reduces the incidence of zoster and PHN, it has not been shown to be protective in other VZV-associated diseases. The characteristic theme in these diseases is persistent, VZV-induced inflammation that results in tissue damage. Thus, this Program Project, composed of 3 Projects and 2 Cores (Administrative and Scientific) will: determine the role of VZV in persistent vascular inflammation that characterizes giant cell arteritis (GCA), the most common systemic vasculitis in elderly that causes headaches, stroke and blindness; examine epigenetic changes in vascular adventitial fibroblasts in GCA that contribute to a persistent proinflammatory phenotype; and trace the evolution of virus infection and inflammation in multiple clinically relevant tissues up to 6 months post-zoster in a simian model of varicella virus reactivation. Project 1 will determine the proinflammatory environment and identify biomarkers in formalin-fixed, paraffin- embedded temporal arteries from GCA patients (GCA-positive TAs) using a novel, validated RNA sequencing strategy that provides complete cellular and viral transcriptome expression profiles. This Project will also determine VZV antigen specificity of T cells isolated from GCA-positive TAs acquired immediately at biopsy. Project 2 tests the hypothesis that adventitial fibroblasts isolated from GCA-positive TAs undergo epigenetic reprogramming such that they are proinflammatory, raising the possibility of treatment with histone deacetylase inhibitors. Project 3 uses a primate model to determine critical virus-host immune cell interactions within multiple tissues at multiple times post-zoster, a study which is otherwise impossible to conduct in humans since VZV-infected tissue at defined times post-zoster is not available. The success of this Program Project is ensured by: 1) collaborations among clinicians and scientists with expertise in VZV biology, immunology, epigenetics, bioinformatics, biostatistics and ophthalmology; 2) prior establishment of proposed protocols; and 3) availability of fresh TA biopsies from multiple hospitals/clinics in the Rocky Mountain Region and access to primate tissues through collaborations with Tulane National Primate Research Center. Together, the studies hold great translational promise since they will provide valuable information about the mechanisms leading to persistent VZV-induced inflammation and tissue damage, thereby providing new therapeutic targets to reduce/prevent clinical disease predominantly affecting the vulnerable aging population.